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Myocyte-specific overexpression of NOS3 prevents endotoxin-induced myocardial dysfunction in mice

Endotoxemia can cause profound myocardial dysfunction contributing to hypotension and shock. Overproduction of nitric oxide (NO) has been implicated as a cause of the myocardial dysfunction of sepsis. Here, we tested the hypothesis that myocyte-specific overexpression of NO synthase 3 (NOS3) can prevent cardiac dysfunction in endotoxin-challenged mice.

Echocardiographic measurements were obtained before and 4 and 7 h after intraperitoneal challenge with endotoxin (Escherichia coli 0111:B4 lipopolysaccaride 50 mg/kg) in wild-type C57BL6 mice (WT) and WT mice with myocyte-specific overexpression of NOS3 (TG), using a 13-MHz ultrasound probe (Sequoia, Acuson, Mountain View, CA). Invasive measurements of LV pressure and volume were obtained with a 1.4F pressure-volume catheter (SPR-839, Millar Instruments, Houston TX) (7 h after challenge with endotoxin or saline).

At baseline, WT and TG mice had comparable measures of LV function. However, as assessed by echocardiography, the endotoxin-induced decrease in LV fractional shortening was attenuated in TG mice (from 54 ± 1 to 40 ± 1%) as compared to WT mice (from 56 ± 1 to 31 ± 2%). Invasive hemodynamics revealed that, compared to saline-challenged mice, dP/dtmax and cardiac output (CO) were markedly impaired in WT but not in TG 7 h after endotoxin challenge (Table 1).

Table 1 Cardiac function at baseline and 7 h after endotoxin-challenge in WT and TG mice

Myocyte-specific overexpression of NOS3 prevented endotoxin-induced reduction of minimally load-independent measures of LV function, including maximal power divided by end-diastolic volume (PMXEDV), dP/dtmax divided by instantaneous pressure (dP/dtmax/IP) and LV end-systolic elastance (Ees).

These results suggest that myocyte-specific overexpression of NOS3 confers protection against endotoxin-induced myocardial dysfunction.

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Correspondence to Emmanuel Buys.

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Keywords

  • Nitric Oxide
  • Myocardial Dysfunction
  • Endotoxin Challenge
  • Intraperitoneal Challenge
  • Invasive Hemodynamic